tbuckley/cabot-search huggingface dataset:
Abstract 6790: The peptide vaccine revived in cancer immunotherpay: a novel peptide vaccine platform for effective cancer immunotherpay
Authors: Dongho Kim, SeungHwan Lee
Journal: Cancer Research (2023)

Abstract The production of tumor-specific T cells is essential for cancer immunotherapy. Due to the low cost and ease of CMC, peptide vaccines have been suggested as effective immunotherapy for cancer. A variety of peptide vaccines have been designed and tested in clinical trials for decades. However, most clinical trials of peptide vaccines have failed for several reasons. Poor stability of peptides, use of inappropriate adjuvants, lack of co-delivery of peptides and adjuvants, and immunosuppression by the tumor microenvironment. We tried to solve the problems that lead to failure and developed effective platform technologies for them. The first problem was the choice of vaccine adjuvants. Poly IC and its derivatives are known to induce antigen-specific Th1 and CTL responses. Since Th1-type immunity is essential for the elimination of intracellular pathogens or tumors, they may be suitable as the adjuvant for peptide vaccines. Despite several limitations of poly IC and its derivatives, such as high heterogeneity, inconsistent activity, poor stability, and unpredictable in vivo kinetics, they still serve as major adjuvants in numerous clinical trials. A novel and defined TLR3 agonist called NexaVant (NVT) was developed as an alternative to them. NVT induces a stronger anti-cancer efficacy compared to the known TLR agonists through multiple advantages of homogeneity, stability, and quantitative in vivo kinetics. Second, the stability of peptides was dramatically improved by a peptide/adjuvant complex formation. When a cationic peptide domain is introduced into the epitope together with an epitope processing domain, the peptide and adjuvant can form a nanocomplex by a simple charge interaction. And this complex improves the stability of the peptide which leads to improvement of the T cell immunity. Third, suppression of T cell immunity in cancer was mitigated by Treg modulation in the presence of a known chemotherapeutic drug. When this combination therapy of the vaccine and chemical was applied to various animal models, a strong anticancer effect was obtained by increasing T cell immunity and suppressing Treg. The same therapeutic effect was shown in several terminal stage tumor models with strong T cell memory regardless of whether the epitope was self or foreign originated. Citation Format: Dongho Kim, SeungHwan Lee. The peptide vaccine revived in cancer immunotherpay: a novel peptide vaccine platform for effective cancer immunotherpay [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6790.
Abstract 2585: Mutant p53 gains oncogenic functions through a cytosolic DNA response
Authors: Mei Zhao, Tianxiao Wang, Frederico O. Gleber-Netto, Zhen Chen, Daniel J. McGrail, Javier A. Gomez, Wutong Ju, Mayur A. Gadhikar, Wencai Ma, Li Shen, Ximing Tang, Sen Pathak, Maria G. Raso, Jared Burks, Shiaw-Yih Lin, Jing Wang, Asha S. Multani, Curtis R. Pickering, Junjie Chen, Jeffrey N. Myers, Ge Zhou
Journal: Cancer Research (2023)

Abstract TP53 mutations are the most common cancer driver mutations among all cancers. Although some TP53 mutations lead to a loss of function of wild-type p53, many other TP53 mutations confer gain-of-function (GOF) activities, which promote cancer cell metastasis and pro-tumorigenic inflammation. Despite that many functional models of GOF mutant p53 (mutp53) have been proposed previously, the mechanisms involved in mutp53 GOF still remain largely elusive. Here we show that by directly targeting minichromosome maintenance complex component 5 (MCM5), a component of the hexametric DNA helicase MCM2-7 complex, GOF mutp53 predisposes cancer cells to replication stress and chromosomal instability, which leads to a tumor cell-autonomous and stimulator of interferon genes (STING)-dependent cytosolic DNA response that activates downstream non-canonical nuclear factor kappa light chain enhancer of activated B cell (NC-NF-κB) signaling. Furthermore, our results demonstrate that GOF mutp53-activated tumor cell-intrinsic STING-NC-NF-κB signaling not only stimulates tumor cell metastasis, but also promotes tumor immune resistance through fostering an immunosuppressive tumor microenvironment. Therefore, our findings that mutp53 exerts its GOF role through pro-tumorigenic MCM5-CIN-STING-NC-NF-κB signaling highlight the importance of TP53 and its inactivation in cancer genome evolution of genomic instability that drives tumor development and progression. Citation Format: Mei Zhao, Tianxiao Wang, Frederico O. Gleber-Netto, Zhen Chen, Daniel J. McGrail, Javier A. Gomez, Wutong Ju, Mayur A. Gadhikar, Wencai Ma, Li Shen, Ximing Tang, Sen Pathak, Maria G. Raso, Jared Burks, Shiaw-Yih Lin, Jing Wang, Asha S. Multani, Curtis R. Pickering, Junjie Chen, Jeffrey N. Myers, Ge Zhou. Mutant p53 gains oncogenic functions through a cytosolic DNA response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2585.
Abstract 6729: Urea cycle metabolism is disturbed in Fibrolamellar carcinoma
Authors: Mahsa Shirani, Solomon Levin, Michael D. Tomasini, James Knox, Bassem Shebl, David Requena, Jackson Clark, Søren Heissel, Hanan Alwaseem, Rodrigo Surjan, Ron Lahasky, Henrik Molina, Barbara Lyons, Rachael D. Migler, Philip Coffino, Sanford M. Simon
Journal: Cancer Research (2023)

Abstract In fibrolamellar hepatocellular carcinoma (FLC), hyperammonemic encephalopathy is a common occurrence and occasionally causes death. Using mass spectrometry, we quantitatively analyzed the proteomes of FLC patient’s tumor and adjacent normal, to find pathways that are changed in FLC. These data identified multiple proteins that were altered in the proteome, among these, enzymes involved in metabolism of ammonia. These results were confirmed with immunofluorescence demonstrating that these alterations occur in all tumor cells. These results suggest that FLC cells have defects in the two primary ammonia detoxification pathways in the liver, which are responsible for detoxification of 70% of the ammonia in the body: 1) consumption of ammonia by glutamine synthetase (GLUL), and 2) addition of ammonia by ornithine carbamoyltransferase (OTC) to the urea cycle. Additionally, they also generate extra ammonia because of upregulation of glutaminase (GLS). This was tested with a targeted metabolomics of the reactants and products of these enzymes. The results were consistent with both a loss of the two pathways for consumption of ammonia activation of a pathway for generating ammonia. This production of ammonia is consistent with the observation that surgical resection of fibrolamellar reduces the ammonia in patients. All FLC patients with hyperammonemic encephalopathy and documented urine test results showed increased urinary orotic acid, evidence of blockage of the OTC pathway. This study implies that hyperammonemic encephalopathy in FLC may require alternatives to commonly used therapies. Citation Format: Mahsa Shirani, Solomon Levin, Michael D. Tomasini, James Knox, Bassem Shebl, David Requena, Jackson Clark, Søren Heissel, Hanan Alwaseem, Rodrigo Surjan, Ron Lahasky, Henrik Molina, Barbara Lyons, Rachael D. Migler, Philip Coffino, Sanford M. Simon. Urea cycle metabolism is disturbed in Fibrolamellar carcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6729.
Abstract 5181: The role of Neuropilin-1 signaling in CD4 conventional T cell immune function in non-small cell lung cancer
Authors: Bitta P. Kahangi, Raymond J. Lim, Jensen Abascal, William P. Crosson, Edgar Perez Reyes, Camelia Dumitras, Linh M. Tran, Kostyantyn Krysan, Ramin Salehi-Rad, Steven M. Dubinett, Bin Liu
Journal: Cancer Research (2023)

Abstract Despite advances in therapy, lung cancer remains the leading cause of cancer related deaths. In non-small cell lung cancer (NSCLC), a subset of tumor-infiltrating CD4 T cells express Neuropilin-1 (NRP1), a transmembrane protein that binds to multiple ligands with diverse functions in tumor and immune cells. Recent studies reveal that NRP1 can be induced upon T cell receptor stimulation and that NRP1 signaling promotes increased stabilization and function of CD4+ FoxP3+ regulatory T cells (Tregs), while signaling on CD8 T cells results in inhibition of CD8 T cell migration and cytotoxicity; therefore, NRP1 is implicated as a newly defined immune checkpoint protein. The functional role of NRP1 in CD4+ FoxP3- T conventional cells (CD4 Tconv) and the ligands involved are largely unexplored. We have found that human lung cancer malignant pleural effusions (MPE) from a subset of metastatic lung cancer patients contain both NRP1+ and NRP1- CD4 Tconv cells, providing a relevant clinical setting to study the function of NRP1 in human T cells. Our preliminary studies reveal that MPE-derived NRP1+ CD4 Tconv cells have altered expression of CD25, suggestive of a more activated state as compared to that of NRP1- CD4 Tconv cells. Additionally, we have observed disproportionate cell death of NRP1+ CD4 Tconv cells that can be partially rescued with anti-NRP1 monoclonal antibodies (mAbs). Surviving NRP1+ cells are more likely to express PD-1 and secrete effector cytokines. In our murine NSCLC model carrying key driver mutations KrasG12D P53−/− Lkb1−/− and higher tumor mutational burden (KPL-3M), analysis of tumor-infiltrating CD4 Tconv cells confirm that NRP1+ CD4 T cells are preferentially found within tumors and with higher PD-1 expression as compared to NRP1- cells. Furthermore, treatment with anti-NRP1 mAbs confers anti-tumor efficacy in this model, indicating that NRP1 is a functionally important inhibitor of host anti-tumor immune responses. These data suggest that CD4 Tconv cells expressing NRP1 are activated but prone to cell death, warranting further investigation into its potential as a therapeutic target for NSCLC. Citation Format: Bitta P. Kahangi, Raymond J. Lim, Jensen Abascal, William P. Crosson, Edgar Perez Reyes, Camelia Dumitras, Linh M. Tran, Kostyantyn Krysan, Ramin Salehi-Rad, Steven M. Dubinett, Bin Liu. The role of Neuropilin-1 signaling in CD4 conventional T cell immune function in non-small cell lung cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5181.
Abstract 5163: Local delivery of mRNA immunotherapy encoding HPV16 antigen, IL-12, and LIGHT/TNFSF14 results in superior immunogenicity and tumor clearance in a murine model of HPV16-driven cancer
Authors: Weiqun Liu, Diane M. Da Silva, Edward E. Lemmens, Colin J. McKinlay, Sangeeta Nath, Meredith L. Leong, Samuel Deutsch, W. Martin Kast, Ole Audun W. Haabeth
Journal: Cancer Research (2023)

Abstract While intramuscular vaccination with HPV16 antigens has been shown to induce robust tumor-specific immune responses in the periphery, this has led to limited efficacy in the clinic. One potential explanation is the lack of sufficient infiltration of antigen-specific T cells into the tumor. The few T cells that make their way into the tumor are met with a plethora of negative signals that suppress their activity and abrogate local T cell expansion. To overcome this limitation of intramuscular cancer vaccines, we have developed an approach using in situ vaccination with a combination of immune modulators and tumor antigens, all encoded by mRNAs and delivered using nanoparticles. In this study, we show the superior efficacy and immunogenicity of a locally delivered mRNA cancer vaccine over that of an intramuscular HPV16 cancer vaccine. Both routes of administration result in robust induction of antigen-specific T cells, but local administration of mRNA-encoded antigens and immune modulators also resulted in enhanced infiltration of immune cells into the tumor, local Th1/M1 cytokine induction, and more-complete tumor clearance. Specifically, we found that the inclusion of the immunomodulators IL-12 and TNFSF14/LIGHT enabled tumor clearance in a murine tumor model. While tumors treated with mRNA-encoded HPV16 antigen alone induced robust systemic antigen-specific responses, minimal levels of local T cell expansion and infiltration, proinflammatory cytokine induction, and tumor control were observed. By contrast, tumors treated with mRNA-encoded HPV16 antigen, IL-12p70, and TNFSF14 completely cleared large established HPV16 expressing tumors with long-lasting recurrence free survival and immune memory. This observation was replicated in in a second murine tumor model, confirming the superior potency of locally delivered mRNA cancer vaccines in combination with immunomodulators. Consequently, we are developing a locally administrated mRNA therapy for the treatment of patients with cervical intraepithelial neoplasia (CIN). Citation Format: Weiqun Liu, Diane M. Da Silva, Edward E. Lemmens, Colin J. McKinlay, Sangeeta Nath, Meredith L. Leong, Samuel Deutsch, W. Martin Kast, Ole Audun W. Haabeth. Local delivery of mRNA immunotherapy encoding HPV16 antigen, IL-12, and LIGHT/TNFSF14 results in superior immunogenicity and tumor clearance in a murine model of HPV16-driven cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5163.
Abstract 3631: Infiltrating Bruton’s tyrosine kinase expressed B cells effects on prostate cancer metastasis
Authors: Crystal Byrd, Geou- Yarh Liou
Journal: Cancer Research (2023)

Abstract Prostate cancer is the most common type of cancer found in senior males and is the 2nd leading cause of cancer death in American males. Although prostate cancer grows slowly within the prostate glands, because of a lack of efficient treatments at the appropriate timing, cancer cells eventually become aggressive and metastatic. The progression of cancer is supported by many factors, such as signals received from surrounding cells, like B cells and other effector cells. B cells play a role as a part of the adaptive immune system to produce antibodies. To become mature B cells, they rely on activation of a non-receptor kinase, Bruton’s Tyrosine Kinase (BTK). Preliminary data from our lab showed that in the prostate cancer tissues, more infiltrated B cells expressing BTK were present nearby the prostate cancer cells. Upon this finding, we hypothesize that BTK expressed B cells will support the survival of prostate cancer cells through BTK signaling. In this study, we will overexpress BTK in B cells to study the proliferation and migration of prostate cancer cells through a co-culture system. Our findings will show an increase in migration of prostate cancer cells when cultured with BTK expressed B cells. In the future, we will validate the importance of BTK in regulating prostate cancer migration and invasion; and identify their mechanisms. Our overall findings from this project would reveal key elements of the signaling pathways of BTK expressed B cells to promote prostate cancer migration. Citation Format: Crystal Byrd, Geou- Yarh Liou. Infiltrating Bruton’s tyrosine kinase expressed B cells effects on prostate cancer metastasis. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3631.
Abstract 5964: Context-dependent induction of interferon signaling by CD11b agonists supports anti-tumor immunity in mouse models and human cancer patients
Authors: Xiuting Liu, Graham Hogg, Chong Zuo, John Baer, Varintra Lander, Liang Kang, Nicholas Borcherding, Brett Knolhoff, Robin Osterhout, Anna Galkin, Jean Bruey, Laura Carter, Cedric Mpoy, Julie Schwarz, Haeseong Park, Vineet Gupta, David DeNardo
Journal: Cancer Research (2023)

Abstract Chronic activation of inflammatory pathways and suppressed interferon signaling are hallmarks of myeloid cells in immunosuppressive tumors that drive poor responsiveness to conventional and immune therapies. Previous studies have identified agonistic activation of the CD11b integrin as a potential strategy to enhance anti-tumor immunity. However, the mechanisms by which CD11b-agonism reprogram tumor immunity are poorly understood, and this may impair patient selection and identification of effective treatment combinations. Here we will use a combination of in vitro systems, animal models, and samples from first in human clinical trials of the CD11b-agonist to identify the mechanism of action of this approach and identify combinations for further testing. CD11b agonism alters tumor-associated macrophage (TAM) phenotypes by simultaneously repressing NFκB/IL1-signaling and activating interferon (IFN) gene expression. Repression of NFκB/IL-1 signaling was due to rapid degradation of p65 protein by the proteosome, contributing to suppressing myeloid cells infiltration. In contrast, CD11b agonism triggers mitochondrial dysfunction to stimulate STING-induced, STAT1-mediated interferon signaling, contributing to macrophages-augmented anti-tumor T cell immunity. Tissues from phase I clinical trials shows that CD11b agonist activates STING and STAT1 signaling in TAMs in human tumors, which is in consistent with preclinical data. Furthermore, combining CD11b agonism with cytotoxic therapies, STING agonist or TLRs agonists leads to robust anti-tumor activity in PDAC models. These studies pave the way for mechanism-based therapeutic combination strategies in cancer patients. Citation Format: Xiuting Liu, Graham Hogg, Chong Zuo, John Baer, Varintra Lander, Liang Kang, Nicholas Borcherding, Brett Knolhoff, Robin Osterhout, Anna Galkin, Jean Bruey, Laura Carter, Cedric Mpoy, Julie Schwarz, Haeseong Park, Vineet Gupta, David DeNardo. Context-dependent induction of interferon signaling by CD11b agonists supports anti-tumor immunity in mouse models and human cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5964.
Abstract 4344: Consensus genomic subtypes of gastric adenocarcinoma and their therapeutic implication
Authors: Yun Seong Jeong, Young-Gyu Eun, Sung Hwan Lee, Sang-Hee Kang, Sun Young Yim, Eui Hyun Kim, Joo Kyung Noh, Bo Hwa Sohn, Ju-Seog Lee
Journal: Cancer Research (2023)

Abstract Background: Gastric adenocarcinoma (GAC) is heterogeneous lethal disease in genomic and clinical level. Although the clinical relevance of genomic and molecular subtypes of GAC has been demonstrated, their translation to the clinic has been hindered by discrepancies in classification methods. We aim to examine a consensus of genomic subtypes and correlate them with clinical outcomes. Method: We collected genomic data from 2527 GAC tumors and divided the data into discovery (n = 1427) and validation sets (n = 1100). By integrating 8 previously established genomic subtype algorithms, we identified 6 clinically and molecularly distinct genomic consensus subtypes (CGSs) in discovery set. For validation of clinical significance of new subtypes, we constructed GAC predictor of integrated consensus subtype with 120 genes (GPICS120) and applied it to validation data set. In systematic analysis of genomic and proteomic data, we estimated potential response rate of each subtype to standard and experimental treatments such as radiation therapy, target therapy, and immunotherapy and further validated their functional significance in cell line models. Results: Among identified 6 subtypes. CGS1 is characterized by poorest prognosis, very high stem cell characteristics, and high IGF1 expression, but low genomic alterations. CGS2 showed canonical epithelial gene expression patterns. CGS3 and CGS4 are characterized by high copy number alterations and low immune activity. However, CGS3 and CGS4 are different in high HER2 activation (CGS3) and SALL4 and KRAS activation (CSG4). CGS5 has highest mutation burden and moderately high immune activity that is characteristics of MSI-high tumors. Most of CGS6 tumors are EBV-positive and shows extremely high methylation and high immune activity. Most interestingly, CSG1 is most responsive to immunotherapy while CGS3 is significantly associated with benefit of chemoradiation therapy due to high basal level ferroptosis. In addition, we also identified potential therapeutic targets for each subtype. Conclusion: Consensus subtype is robust classification system and can be the basis for pre-clinical investigation of subtype-based targeted interventions and future clinical trials. Citation Format: Yun Seong Jeong, Young-Gyu Eun, Sung Hwan Lee, Sang-Hee Kang, Sun Young Yim, Eui Hyun Kim, Joo Kyung Noh, Bo Hwa Sohn, Ju-Seog Lee. Consensus genomic subtypes of gastric adenocarcinoma and their therapeutic implication. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4344.
Abstract 4652: A cellular and transcriptomic dissection of the human breast for studying mechanisms of cell and tissue function
Authors: Katelyn Del Toro, Rosalyn W. Sayaman, Kate Thi, Yamhilette Licon-Munoz, William C. Hines
Journal: Cancer Research (2023)

Abstract A fundamental question in biology, central to our understanding of cancer and other pathologies, is determining how different cell types coordinate to form and maintain tissues. Recognizing the distinct features and capabilities of the cells that compose these tissues is critical. Unfortunately, the complexity of tissues often hinders our ability to distinguish between neighboring cell types and, in turn, scrutinize their transcriptomes and generate reliable and tractable cell models for studying their inherently different biologies. A lack of comprehensive methods to identify, isolate, and culture each cell type from many tissues have impeded progress. Here, we will describe such a method for the breadth of cell types composing the human breast. Furthermore, we have sequenced mRNAs from each purified population and investigated transcriptional patterns that reveal their distinguishing features. These analyses have exposed differentially expressed genes and enriched biological pathways that capture the essence of each cell type, along with transcripts that display intriguing expression patterns. These data, analytic tools, and transcriptional analyses form a rich resource whose exploration provides remarkable insights into the inner workings of the cell types composing the breast, thus furthering our understanding of the rules governing normal cell and tissue function. Citation Format: Katelyn Del Toro, Rosalyn W. Sayaman, Kate Thi, Yamhilette Licon-Munoz, William C. Hines. A cellular and transcriptomic dissection of the human breast for studying mechanisms of cell and tissue function. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4652.